Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention.

Abstract

Expression of cyclooxygenase-2 (COX-2) has been reported to be elevated in human colorectal adenocarcinoma and other tumors, including those of breast, cervical, prostate, and lung. Genetic knock-out or pharmacological inhibition of COX-2 has been shown to protect against experimentally-induced carcinogenesis. Results from epidemiological and laboratory studies indicate that regular intake of selective COX-2 inhibitors reduces the risk of several forms of human malignancies. Thus, it is conceivable that targeted inhibition of abnormally or improperly elevated COX-2 provides one of the most effective and promising strategies for cancer chemoprevention. The COX-2 promoter contains a TATA box and binding sites for several transcription factors including nuclear factor-kappaB (NF-kappaB), nuclear factor for interleukin-6/CCAAT enhancer-binding protein (NF-IL6/C/EBP) and cyclic AMP response element (CRE) binding protein. Upregulation of COX-2 is mediated by a variety of stimuli including tumor promoters, oncogenes, and growth factors. Stimulation of either protein kinase C (PKC) or Ras signaling enhances mitogen-activated protein kinase (MAPK) activity, which, in turn, activates transcription of cox-2. Celecoxib, the first US FDA approved selective COX-2 inhibitor, initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, has been reported to reduce the formation of polyps in patients with familial adenomatous polyposis. This COX-2 specific inhibitor also protects against experimentally-induced carcinogenesis, but the underlying molecular mechanisms are poorly understood. The present review covers the signal transduction pathways responsible for regulating COX-2 expression as novel molecular targets of chemopreventive agents with celecoxib as a specific example.

• Authors: Kyung-Soo Chun, Young-Joon Surh
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 68 Issue 6 Pg. 1089-100 (Sep 15 2004) ISSN: 0006-2952 [Print] England
• PMID: 15313405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Isoenzymes
• Membrane Proteins
• Pyrazoles
• Sulfonamides
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Celecoxib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Celecoxib
• Chemoprevention
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Isoenzymes (genetics, metabolism)
• Membrane Proteins
• Neoplasms (prevention & control)
• Prostaglandin-Endoperoxide Synthases (genetics, metabolism)
• Pyrazoles
• Signal Transduction (drug effects, genetics)
• Sulfonamides (pharmacology, therapeutic use)
• Transcription, Genetic (drug effects)